Tobacco use is the single leading preventable cause of death in the United States. Nicotine is an alkaloid derived from the tobacco plant that is primarily responsible for smoking's psychoactive and addictive effects. Immunotherapy may potentially be useful to prevent and/or treat addiction to nicotine and other drugs of abuse. Nicotine-specific antibodies would bind and sequester nicotine in the serum, thus preventing nicotine from reaching the brain as antibodies are too large to cross the blood brain barrier. Haptens, such as nicotine, can be made immunogenic by conjugation to carrier proteins to make nicotine vaccines. A number of studies have shown that, in animals, nicotine vaccines reduce the distribution of nicotine to the brain, attenuate the locomotor and stimulus properties of nicotine and prevent nicotine from relieving nicotine abstinence syndrome. In humans, such a vaccine may be an effective aid in smoking cessation and reduce the rate/time to relapse. Nabi has completed two studies of its proprietary nicotine vaccine NicVAXTM; one Phase 1 clinical trial (Nabi 4502) to evaluate safety in non-smoking adults, and one Phase 1/2 clinical trial in 21 smokers and 9 exsmokers (Nabi 4503). We have fully enrolled a multi-site, NIDA-funded Phase 2 clinical trial in 63 smokers (Nabi 4504). An additional Phase 2 clinical trial (Nabi 4505) in 30 smokers designed to compare 3 dosing schedules will be started in April, 2004. These trials are described more fully below. The results from these studies will form the basis for the additional efficacy and safety studies proposed in this application. The specific aim of this proposal is to demonstrate in a proof of concept, Phase 2, clinical trial of NicVAX in smokers (Nabi 4506) both the efficacy as measured by smoking cessation rates and the safety of the vaccine. Prior to initiating Nabi 4506 a new lot of NicVAX will be manufactured and tested for safety and immunogenicity in Nabi 45SI.